The Blood-Brain Barrier (BBB) presents a significant challenge for effective drug delivery. The BBB is a diffusion barrier, a selective semipermeable border that regulates the transit of pathogens and toxins between the bloodstream and the brain. It comprises of tightly packed layers formed of endothelial cells, astrocytic endfeet, and a basement membrane. In a healthy brain, the BBB plays a vital role in maintaining an optimal environment for neuronal functioning and acts as an interface between the circulation and central nervous system (CNS). In a diseased brain, however, the BBB becomes radically disrupted.
Brain diseases such as brain cancers and central nervous system disorders are among the most prevalent and poorly treated conditions. The BBB hinders the treatment of these diseases, by preventing the entry of conventional methods of drug delivery and other therapeutics to the brain. Given the complexity of the brain and its impermeable barrier, means that the time taken to develop CNS drugs is a considerably longer and more arduous process. Nevertheless, there are approximately 76 pharmaceutical and biotechnology companies currently developing cutting edge technologies to advance drug delivery methods through the BBB. The market is even projected to reach an impressive 4.6 billion USD by 2026. Some of the most prolific innovations are coming from companies such as CarThera and Bristol-Myers Squibb, universities including Northwestern, MIT, Harvard, and research initiatives such as the European Union’s Horizon project.
The Challenge of Delivery to the Blood-Brain Barrier:
So, what about the BBB is so challenging? A physiological hurdle, the BBB obstructs around 95% of molecules during the drug development stage. Most macromolecules are unable to penetrate the brain’s endothelium. Only small and lipid-soluble molecules that weigh less than 400 Da can successfully cross the BBB, significantly restricting the number of molecular candidates available for delivery. In other words, therapeutic molecules that may prove effective in diagnosis and treatment fail to obtain clinical approval because they cannot reach their cerebral target in adequate amounts. Integral to overcoming the resistance of the BBB is a thorough understanding of the delicate intricacies of the brain as an interface and how its function becomes rapidly compromised under pathological conditions such as multiple sclerosis, Parkinson’s disease, seizures, strokes, and Alzheimer’s.
Improving the success rates of neuropharmacology requires advanced examination of the body’s neurovascular units and their role in the BBB’s resistance. Neurovascular units describe the relationship between brain cells and their blood vessels. Peter Westenskow, Senior Principal Scientist and Section Head at F. Hoffmann-La Roche Ltd, claims that “scientists must find out how to restore normal homeostasis to a neuron so that it stops sending signals that tell the vasculature to misbehave”. He continues, “it is vital to learn as much as possible about every single neuron in these neurovascular units, learn what they like to eat, how they respond to stress, learn what other supporting cells are present, and how they contribute to the issue”. Therefore, it is vital to think of the neurovascular unit as a whole, an interconnected and dependent interface instead of a unitary and independent construct.
Advances in Technology: Overcoming the Blood-Brain Barrier
Developing optimised BBB models and technologies is a key area of research for many scientists working within the field. And there are a number of exciting developments being made in the advancement of neuropathological drug transporters. We look at the top 3 most promising of these technologies and devices:
1.) Ultrasound Implant: An ultrasound implant is currently under development with the aim to facilitate an on-demand opening of the BBB during drug delivery. In particular, the intracranial implant opens the blood-brain barrier before or after the injection of therapeutic agents. By emitting low-intensity pulsed ultrasound waves, this device will temporarily increase the permeability of the blood vessels in the brain and allow for the advancement of treatments for severe brain disorders including Alzheimer’s diseases, brain metastasis, and glioblastoma. It will also reduce the side effects caused by chemotherapy and facilitates a 7-time higher rate of targeted delivery to the brain.
One such company to develop this highly anticipated implant is the French MedTech corporation, CarThera. A clinical-stage company, CarThera are currently initiating their ultrasound Implant, called the SonoCloud. In 2020 they teamed up with Northwestern University and Bristol-Myers Squibb to run a phase 1/2 clinical trial to test the device’s effectiveness when used in combination with the drug Abraxane on patients with recurrent glioblastoma. The product is expected to launch by 2023.
2.) Nanomedicine: The delivery of nanoparticles is an increasing area of development in BBB engagement. Nanomedicine applies the tools and understanding of nanotechnologies to both prevent and treat diseases. Nanotechnologies are devices that use nanoscale materials (particles that are 1 to 100 nanometres in size) to interact with cells and their tissues on a molecular level and have the potential to carry out multiple specific functions simultaneously. Cutting-edge research has now found that nanomedicine can successfully facilitate siRNA delivery across the BBB to treat traumatic brain injury (TBI).
In January 2021, researchers at MIT and Harvard Medical School used engineered nanoparticles that contained siRNA fabrications to inhibit neurodegeneration. By modulating surface chemistry and coating density, scientists were able to adjust the entry of nanoparticles across the BBB through tight junctions. Results showed that the number of nanoparticles present in the TBI mouse model was three times higher than in those using traditional methods. Other key players in the use of nanotechnologies include the biotech company CNS Pharmaceuticals, Inc who with MD Anderson, is in the process of investigating a new class of subnanomolar DNA-binding agents (WP1244). Pre-clinical tests have found the agents’ successful penetration of the BBB with no observable toxicity in animal models.
3.) Nose-to-Brain Patch: Funded by the European Union’s Horizon 2020 program, the N2B-patch project or nose-to-brain patch is a practical and minimally invasive drug delivery system. It transports biologics drugs directly from the nasal cavity to the brain via a medical device in order to bypass the BBB. The carrier consists of a hydrogel-formulated application and offers a painless and more efficient administration. An innovative procedure, the N2B patch aims to treat multiple sclerosis and as of 2021, received a rank of 5 on the technology readiness level.
The field of potential applications for the N2B patch is vast, with researchers confident in its prospective to treat further CNS conditions. In particular, the European Union hopes that the program will impact social sustainability by ensuring improved drug delivery for hundreds of thousands of people. The patch also promotes the use of personalised medicines, which has the potential to make the required interventions more efficient. By bringing a new medical device to the market, the N2B project predicts its ability to create a manifold of new work opportunities for European distribution and manufacturing companies.
Despite its notorious difficulty, the BBB is an ever-evolving area of industry development. The strives taken to overcome the technological and delivery challenges posed by the barrier and its near-inviolable diffusion is encouraging. Ultrasound techniques, nanomedicine, and the nose-to-brain patch bring scientists one step closer to achieving the optimal delivery of therapeutics to the BBB every single day. But it is not only the technological advances in the industry that are proving ground-breaking. Research discoveries are also gaining momentum. Only in April this year, scientists at the University of Pennsylvania found a link between the BBB and the onset of psychological disorders such as schizophrenia. At Oxford Global, we believe that these exciting developments and breakthroughs mean it will only be a matter of time before scientific innovation acquires the foresight to defeat the BBB once and for all.